Localized phosphoinositide metabolism regulates STIM1/ORAI1 fast inactivation

Store-operated Ca²⁺ entry (SOCE) is central for maintaining cellular Ca²⁺ homeostasis, and it is initiated by the depletion of Ca²⁺ in the endoplasmic reticulum (ER) and activation of stromal interaction molecule 1 (STIM1). STIM1 acts as an ER Ca²⁺ sensor and engages with plasma membrane ORAI1 channels to facilitate ORAI1 activation and Ca²⁺ influx. Here, we found that STIM1 forms a complex with myotubularin-related protein 7 (MTMR7) to regulate ORAI1 inactivation during prolonged Ca²⁺ entry. MTMR7 alters plasma membrane PI(3,5)P2 and PI(4,5)P2 levels, increasing ORAI1 inactivation and decreasing SOCE. Loss of catalytic phosphatase function of MTMR7 weakens ORAI1 inactivation and enhances SOCE activity, while the disruption of MTMR7 and STIM1 association retains ORAI1 inactivation. The MTMR7/STIM1 complex positions MTMR7 at ER-plasma membrane contact sites to fine-tune lipid signaling, prevent premature STIM1 activation, and modify ORAI1 inactivation. These findings provide insight into novel modes of regulation of ORAI1 inactivation by phosphoinositides (PIPs).